Bioartificial kidneys (BAKs) have been contemplated in order to assist with, or as an alternative to, dialysis, hemofiltration or related blood purification methods. Aebischer and colleagues were the first to propose BAKs, comprising a hemofilter in series with two bioreactor units [27, 33, 34]. It was proposed by these authors that the hemofilter should be in series with 2 bioreactor units and that all three units contained in the BAK would be cartridges containing hollow fiber membranes (HFMs). The hemofilter was to be included to generate hemofiltrate with the blood flowing through the lumina of the HFM, while the bioreactors would contain Madin-Darby canine kidney (MDCK) cells or Lewis lung cancer-porcine kidney 1 (LLC-PK1) cells. Aebischer and colleagues did not construct the proposed BAKs, but did preliminary in vitro studies using membranes and HFMs [27, 33-37].
More recently, work done by Saito et al. [24, 25, 38-41], Humes et al. [1-4, 8, 9], Mao et al. [5] and Wang et al. [6] involves BAKs that contain a hemofilter in series with a single bioreactor having renal proximal tubule cells growing inside the lumen of the HFMs. The hemofiltrate flows through the lumen of the HFMs of the bioreactor, with blood flowing on the exterior side of the HFMs.
In particular, animal studies [1-7] and clinical trials [8, 9] were performed with these two-cartridge BAKs. Thus, with this arrangement, the hemofiltrate (which may also be referred to as ultrafiltrate) flows past the cells in the bioreactor, while the blood is separated from the cells by the semipermeable membrane of the HFMs, mimicking the architecture of the renal proximal tubule. It was expected that the bioreactor unit would replace or simulate functions of the renal proximal tubule. However, in a phase I/lI clinical trial, no clear indication was obtained that proximal tubular-specific functions were contributed by the renal cells [8, 10].
Improved long-term survival in the group of patients that received BAK treatment was observed in a phase II clinical trial involving critically ill patients with acute kidney injury (AKI) [9]; the reasons for this clinical improvement remain unclear [10, 11]. Cytokine levels in serum and plasma were measured in various animal studies and the Phase I/II clinical trial [1, 2, 5-8]. Some changes in cytokine levels suggested that beneficial effects of BAK treatment might be a result of immunomodulatory functions [1, 2, 5-8]. However, the release of cytokines or other immunomodulators from the bioreactor unit has not been investigated, so far. A Phase II b clinical trial failed in 2006 (discussed in [9]), and since then no further clinical trials with BAK have been performed.